Development in mammals is profoundly affected by environmental stimuli. Physical stimuli provided by the mother appear to be most critical for survival and growth. The consequences of disrupting this interaction range from marked suppression of certain neuroendocrine and physiological systems following short periods of separation to retardation of growth and behavioral development during long-term separation. These effects are the result of individual cues from the mother which trigger specific developmental adaptations in the infant. Fundamental questions remain as to the biological nature of this mother-infant interaction. The long-term objective of this laboratory is to understand the neonatal pathophysiology of maternal separation (MS). The current goals are to determine how two key consequences of short-term MS, loss of tactile stimulation (MTD) and food deprivation (MFD) affect neonatal development. The adaptive cellular changes evoked by MTD are organized and initiated by the CNS while the changes caused by MFD are due to the direct regulatory actions of D- glucose on neonatal hepatocyte metabolism. Studies are targeted to elucidate the biochemical and molecular mechanisms mediating the specific alterations in cell function resulting from either MTD or short-term MFD. The specific aims are: (1) to further our understanding of beta-endorphin (betaE) as the prime CNS organizer of the adaptive response in the neonate to MTD. Specifically, to investigate whether CNS betaE itself is the mediator of MTD and whether the effects of MTD or CNS administered betaE on ornithine decarboxylase (ODC) expression occur through CNS epsilon receptors, while those on DNA synthesis and insulin catabolism are mediated by classical opioid receptors, (2) to determine the mechanisms by which MTD suppresses GH secretion normally evoked by serotonin (5-HT). Specifically, we will study the function of 5-HT neurons and receptor subtypes by measuring 5-HIAA accumulation and GH secretion evoked by specific serotoninergic receptor agonists/antagonists during MTD paradigms, and (3) to test the hypothesis that the inhibition of hepatic ODC expression in the preweanling by both MTD and MFD is mediated via a down-regulation of intracellular signal transduction systems. Initial studies will focus on the expression of the immediate early genes c-fos, c-jun and c-myc. The experimental approach is to assess multiple growth-related parameters in developing organs and then to use these measurements as indices of altered functional maturation of these tissues resulting from MTD or MFD. Biological systems studied include: molecular (synthesis of DNA, phosphoinositide and cAMP, and expression of ODC and the proto-oncogenes c-fos, c-jun and c-myc), endocrine (GH, insulin, prolactin and corticosterone), neurotransmitters (5-HT and catecholamines), and opioids (beta-endorphin, dynorphin and enkephalins). Studies to date have clearly established that the rat pup model of maternal deprivation is a productive and important paradigm for investigating the relationship between maternal-infant behavioral patterns and neonatal development, and the consequences of disrupting this interaction as occurs in very premature and in non-organic failure-to- thrive human infants.